This proposal is directed toward understanding how thyroid hormone receptors (TRs) recognize DNA and other proteins, and how thyroid hormone binds to the receptor and alters its regulatory activities. Additional studies will address the questions of what proteins interact with TRs and what the consequences of these interactions are, and what is the overall structure of TR and the effect of T3 on that structure.The proposed studies will explore large-scale expression and purification of the TRalpha ligand-binding domain (LBD) and full-length TRbeta, examine the mechanism of TR interactions with various DNAs and transcript ion factors such as retinoid x receptor (RXR), a rat liver RXR related factor, Pit-1, and a novel 120 kD factor. The investigators will study the functional consequences of these interactions, obtain crystals of the TRalpha LBD complexed with T3 and other ligands, the unliganded TRalpha LBD, and the full-length TRbeta. They will determine the three dimensional structure of the ligand bound TRalpha LBD at 2.8-3.0 angstrom resolution, and of the unbound TRalpha LBD.